Purpose of this Guideline

Purpose of this guideline: This guideline was developed by the New York State Department of Health (NYSDOH) AIDS Institute (AI) for primary care providers and other practitioners who are initiating therapy in nonpregnant, antiretroviral-naïve adults living with HIV. The guideline aims to achieve the following goals:

Provide a clear and concise roadmap to choosing from among several equally efficacious ART regimens based on individual patient characteristics and preferences.

Provide a list of regimens to avoid.

Provide dosing considerations for patients with renal or hepatic impairment and important drug-drug and food interactions.

Integrate current evidence-based clinical recommendations into the healthcare-related implementation strategies of the Ending the Epidemic (ETE) initiative, which seeks to end the AIDS epidemic in NYS by the end of 2020.

The NYSDOH AI is publishing this guideline at a critical time: 1) Initiation of ART is now recommended for all patients diagnosed with HIV infection; 2) Identifying and linking patients with HIV infection to care and treatment that achieves optimal virologic suppression are crucial to the success of New York State’s Ending the Epidemic initiative; and 3) The ability of primary care providers and other clinicians in New York State to properly select initial antiretroviral therapy is key to the successful treatment of patients with HIV infection.

Introduction: The New York State (NYS) Department of Health (DOH) AIDS Institute (AI) Medical Care Criteria Committee (MCCC) recommendations for prescribing antiretroviral therapy (ART) regimens for treatment-naïve, nonpregnant adults (age ≥18 years) with HIV-1 infection and without acquired resistance are based on a comprehensive review of available clinical trial data. (For guidelines specific to treatment of adolescents with HIV, please consult Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV at AIDSinfo.nih.gov.) In formulating its recommendations for New York State, this Committee balanced the strength of published evidence regarding efficacy of treatment regimens with factors that influence adherence, including pill burden, tolerability, and dosing schedule. Preferred regimens are supported by evidence and have favorable adherence profiles, with lower pill burdens, fewer adverse effects, and dosing schedules that may be easier for patients to manage. Ranking of regimens in this manner is designed to inform discussion and decision-making with patients.

How to use this guideline: Tables presenting preferred and alternative regimens appear first (see the Available ART Regimens section of this guideline). To help guide the choice among regimens of similar efficacy, each table includes comments that address selected pertinent issues regarding each regimen, such as limitations based on a patient’s kidney function and drug-drug interactions.

Other sections of the guideline include a review of relevant issues, patient considerations, essential laboratory assessments, and the rationale for the recommendations. Reference to the expanded information is crucial for addressing factors that may be of particular importance when individualizing a patient’s treatment, such as loss of bone mineral density with a regimen that includes tenofovir disoproxil fumarate (TDF) and the conflicting data on cardiac risk with abacavir (ABC); see Specific Factors to Consider and Discuss with Patients in this guideline.

Updates to this Guideline

June 2018

Bictegravir (BIC; Biktarvy) added as a preferred initial ART regimen for patients with CrCl >30 mL/min, with related updates throughout all sections of the guideline.

New footnote (6) added to all regimen tables: “When a ‘rapid start’ or ‘test and treat’ initiation of ART occurs before baseline laboratory test results are available, avoid use of abacavir until a patient’s HLA-B*5701 is confirmed negative.”

General Principles in Choosing an Initial ART Regimen

New citations of evidence added to general conclusions that can be drawn based on currently available evidence: 1) “In a study of ART-naïve patients RAL HD 1200 mg once daily was non-inferior to 400 mg tablets dosed twice daily [Cahn et al. 2017]”; and 2) “In two separate trials of treatment-naïve individuals, TAF/FTC/BIC was non-inferior to both TAF/FTC and DTG [Sax et al. 2017] and ABC/3TC/DTG [Gallant J et al. 2017].”

May 2018

On May 18, 2018, the FDA and the DHHS Antiretroviral Guidelines Panels issued statements in response to preliminary results from a study that reported increased risk of neural tube defects in babies born to mothers taking DTG-based ARV drug regimens at the time of conception [AIDSinfo 2018; FDA 2018].

Until more data become available, DTG-containing regimens should be avoided in any HIV-exposed individual who is or could become pregnant and is not using effective contraception. If there are no alternatives to DTG for individuals of child-bearing potential, then clinicians should strongly advise the use of effective contraception and should obtain a pregnancy test before initiating treatment.

November 2017

Revised the fifth recommendation to add active opportunistic infections to the list of extensive comorbidities that should prompt consultation with a care provider experienced in ART management when selecting an initial ART regimen.

Revised text to state that with full adherence, any of the preferred or alternative regimens should lead to full suppression, including MTRs, which can be used when an STR is not possible or not tolerated. For example, a patient who is HLA-B*5701 positive on medications that have significant drug interactions with cobicistat and who did not tolerate DTG could use TAF/FTC with RAL.

Added reference Cahn P, Kaplan R, Sax PE, et al. 2017.

Table 1: Preferred Initial ART Regimens for Non-Pregnant Adults

Added the regimen “Tenofovir alafenamide/emtricitabine and raltegravir (TAF 25 mg/FTC and RAL HD; Descovy and Isentress HD)” to the “Available as Multi-Tablet Regimens with Once-Daily Dosing” section of table 1.

Moved the regimen “Tenofovir disoproxil fumarate/emtricitabine and raltegravir (TDF/FTC and RAL HD; Truvada and Isentress HD)” to the “Available as Multi-Tablet Regimen with Once-Daily Dosing” section of table 2.

The rating was changed from a BI to BIII for the regimen “Tenofovir alafenamide/emtricitabine and raltegravir (TAF 25 mg/FTC and RAL; Descovy and Isentress)” in the “Available as Multi-Tablet Regimen with Twice-Daily Dosing” section of table 2.

Available ART Regimens

Note: The recommendations in this guideline pertain to initial antiretroviral therapy (ART) regimens for adults with HIV infection who are not pregnant.

Dolutegravir (DTG) Safety Statement, May 2018

On May 18, 2018, the FDA and the DHHS Antiretroviral Guidelines Panels issued statements in response to preliminary results from a study that reported increased risk of neural tube defects in babies born to mothers taking DTG-based ARV drug regimens at the time of conception [AIDSinfo 2018; FDA 2018].

Until more data become available, DTG-containing regimens should be avoided in any HIV-exposed individual who is or could become pregnant and is not using effective contraception. If there are no alternatives to DTG for individuals of child-bearing potential, then clinicians should strongly advise the use of effective contraception and should obtain a pregnancy test before initiating treatment.

Baseline testing is not recommended for either integrase resistance or tropism. (A3)

For patients who have delayed initiation of ART and have engaged in high-risk behaviors associated with acquisition of HIV superinfection, genotypic resistance testing should be repeated before choosing the ART regimen. (B3)

Clinicians or clinical staff should follow up, by telephone or other methods, within 2 weeks after treatment initiation to assess tolerance and adherence. Adherence should be reinforced at regular intervals. (A3)

Clinicians should obtain a viral load test within 4 weeks after initiation to assess response to therapy. (A3)

Available Antiretroviral Agents and Regimens

Each regimen listed below in Tables 1 and 2, preferred and alternative initial ART regimens, and in Table 3, Other ART Regimens, Not Preferred or Alternative, is expected to have excellent efficacy, but they differ in tolerability, possible toxicities, convenience, and the potential for drug-drug interactions, all of which can affect overall adherence and suppression rates.

KEY POINT

In general, a preferred regimen should be selected (Table 1, below), although there may be times when an alternative regimen may be a better choice for an individual patient (Table 2, below).

Based on renal and bone mineral density data from randomized trials of tenofovir alafenamide/emtricitabine/cobicistat/ elvitegravir (TAF/FTC/COBI/EVG) versus tenofovir disoproxil fumarate/emtricitabine/ cobicistat/elvitegravir (TDF/FTC/COBI/EVG) in ART-naïve patients or previously suppressed patients on TDF/FTC/COBI/EVG [Sax et al. 2015; Mills et al. 2016a; Pozniak et al. 2016], this Committee recommends TAF over TDF as part of the backbone in preferred regimens. These data, combined with bioequivalence and switch studies [Zack et al. 2016a; Zack et al. 2016b], provide support for the use of TAF/FTC rather than TDF/FTC when combined with dolutegravir (DTG) or raltegravir (RAL) as part of a preferred regimen. In a study of ART-naïve patients RAL HD 1200 mg once daily was non-inferior to 400 mg tablets dosed twice daily and is thus preferred [Cahn et al. 2017]. This Committee does not yet recommend TAF/FTC in combination with boosted protease inhibitors (PIs), as noted below (see Specific Factors to Consider and Discuss with Patients in this guideline). TDF-containing regimens remain safe and efficacious as alternative regimens (Table 2, below). An integrase strand transfer inhibitor (INSTI) as the third drug is preferred over PIs and non-nucleoside reverse transcriptase inhibitors (NNRTIs) based on tolerability and a lower incidence of drug-drug interactions. Because the use of tenofovir alafenamide/emtricitabine/rilpivirine (TAF/FTC/RPV) is limited by viral load and CD4 parameters and is contraindicated with proton-pump inhibitors (PPIs), this regimen is listed as an alternative regimen (Table 3, below).

Efavirenz (EFV)-containing regimens (see Table 3, below), although efficacious, have been shown to be less well-tolerated than the preferred or alternative regimens in Tables 1 and 2, below. Lopinavir/ritonavir (LPV/RTV)-containing regimens are no longer included among the options for initial treatment because of pill burden and reduced tolerability in comparison with other boosted PIs.

When initiating ART at the time of diagnosis (i.e., “rapid start” or “test and treat”), avoid regimens containing abacavir unless results of HLA B-5701 testing are known to be negative. Similarly, rilpivirine is not appropriate for patients whose viral load has not been confirmed to be <100,000 copies/mL and CD4 count confirmed to be ≥200 cells/mm3.

Initial regimens should be selected on the basis of patient preferences and clinical characteristics, and a preferred regimen should be used whenever possible (Table 1, below). Regimens in the tables below are listed alphabetically. (For more information, including drug trade names, see All FDA-Approved HIV Medications.)

There are three STRs listed as preferred regimens, ABC/3TC/DTG, TAF/FTC/COBI/EVG, and TAF/FTC/bictegrevir (BIC). It is possible that these regimens may contain one or more components that are not appropriate for the individual patient, do not allow for adjustment of individual components for renal function, have significant drug interactions, are poorly tolerated, or may be more expensive than the individual components prescribed separately, particularly if available as generic formulations. With full adherence, any of the preferred or alternative regimens should lead to full suppression, including MTRs, which can be used when an STR is not possible or not tolerated. Cost and access may also be determinative factors. For patients with impaired baseline renal function, separating the drugs into individual components and adjusting each may be appropriate. (For more detailed instructions on dosage adjustments for impaired renal function, see Table 8: ARV Dose Adjustments for Renal and Hepatic Impairment.)

Table 1, below, includes initial ART regimens preferred by this Committee; Table 2 lists alternative initial regimens. Table 3 lists other available ART regimens that this Committee considers neither preferred nor alternative. Within each table, regimens are listed alphabetically. For specific details on choosing a regimen, see the discussions in other sections of this guideline (listed on the left) and/or the package insert for the drugs listed below.

Notes: 1) In all cases, FTC and 3TC are interchangeable when not being used in fixed-dose combinations; 2) Because of their drug-interaction profiles, COBI and RTV should not be considered interchangeable; 3) TAF 10 mg and TAF 25 mg are not interchangeable; 4) Refer to Table 8. ARV Dose Adjustments for Renal and Hepatic Impairment for adjustment based on renal or hepatic function; 5) When dosing RAL once daily use the HD formulation of 600 mg tablets dosed at 1200 mg; 6) When a “rapid start” or “test and treat” initiation of ART occurs before baseline laboratory test results are available, avoid use of abacavir until a patient’s HLA-B*5701 is confirmed negative.

Notes: 1) In all cases, FTC and 3TC are interchangeable when not being used in fixed-dose combinations; 2) Because of their drug-interaction profiles, COBI and RTV should not be considered interchangeable; 3) TAF 10 mg and TAF 25 mg are not interchangeable; 4) Refer to Table 8. ARV Dose Adjustments for Renal and Hepatic Impairment for adjustment based on renal or hepatic function; 5) When dosing RAL once daily use the HD formulation of 600 mg tablets dosed at 1200 mg; 6) When a “rapid start” or “test and treat” initiation of ART occurs before a patient’s viral load and CD4 count are available, avoid use of rilpivirine.

Abacavir/lamivudine and raltegravir
(ABC/3TC and RAL; Epzicom and Isentress)

Initiate only in patients confirmed to be negative for HLA-B*5701.

Consider underlying risk of coronary heart disease.

ABC/3TC once daily and RAL 400 mg twice daily.

B1

Notes: 1) In all cases, FTC and 3TC are interchangeable when not being used in FDCs; 2) Because of their drug-interaction profiles, COBI and RTV should not be considered interchangeable; 3) TAF 10 mg and TAF 25 mg are not interchangeable; 4) Refer to Table 8. ARV Dose Adjustments for Renal and Hepatic Impairment for adjustment based on renal or hepatic function; 5) When dosing RAL once daily use the HD formulation of 600 mg tablets dosed at 1200 mg; 6) When a “rapid start” or “test and treat” initiation of ART occurs before a patient’s viral load and CD4 count are available, avoid use of rilpivirine; if a patient has not been confirmed to be HLA-B*5701 negative, avoid use of abacavir.

General Principles in Choosing an Initial ART Regimen

Goals of ART: The issue of when to start ART was settled with the publication of the START (Strategic Timing of Antiretroviral Treatment) and TEMPRANO (Early Antiretroviral Treatment and/or Early Isoniazid Prophylaxis Against Tuberculosis in HIV-infected Adults) studies early in 2015 [INSIGHT START 2015; TEMPRANO ANRS 12136 2015]. Treatment is now recommended for all patients with confirmed HIV infection regardless of CD4 cell count or viral load (see NYSDOH AI guideline When to Initiate ART). The goal of ART is complete and durable suppression of plasma viremia while minimizing toxicity and maximizing quality of life. Properly selected ART may never require a change or adjustment once started. Treatment interruptions should be avoided [SMART 2006].

Since the approval of zidovudine (ZDV) on March 19, 1987, there have been 28 individual agents approved for the treatment of HIV and one pharmacokinetic enhancer (or booster), cobicistat (COBI), which is currently used to enhance the pharmacokinetics of elvitegravir (EVG), atazanavir (ATV), or darunavir (DRV). Ritonavir (RTV) at treatment doses is poorly tolerated and is used only at lower doses for pharmacokinetic boosting of PIs. An additional 16 FDA-approved fixed-dose combination tablets (FDCs) are also available. These FDCs include so-called “single-tablet regimens,” of which there are seven currently available that provide a complete and effective treatment regimen for HIV that is combined into one pill for use in properly selected individuals. The goal of initial therapy is to start a regimen that suits a patient’s lifestyle and is appropriate given existing baseline medical comorbidities.

Three active drugs from at least two different classes: Although regimen options for treatment-naïve, nonpregnant patients are constantly evolving, the same general principles that were established with the first effective and durable therapies are still true today [Gulick et al. 2000]. Patients should receive three active drugs from at least two different classes. The “backbone” of therapy remains two nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) paired with one of the following: an NNRTI, a boosted PI, or a boosted or unboosted INSTI. In one large meta-analysis, integrase strand inhibitors (INSTIs), were superior to other drug classes as a third drug [Lee et al. 2014], and dolutegravir (DTG) may have specific advantages because of the lack, to date, of documented resistance developing in ART-naïve patients who initiate DTG-containing regimens [Wainberg and Mesplede 2015]. Two other classes of approved medications, entry inhibitors and fusion inhibitors, are not recommended for initial therapy (see Table 5, below) but may have a role in treatment-experienced patients with extensive drug resistance (see All FDA-Approved Medications, including generic and trade names).

TAF, which is a newer pro-drug formulation for tenofovir, was developed as an alternative to TDF and has been approved as part of three single-tablet regimens, TAF 10 mg/FTC/COBI/EVG, TAF 25 mg/FTC/RPV, TAF 25 mg/FTC/BIC [Genvoya 2016; Odefsey 2016], and the fixed-dose combination TAF 25 mg/FTC [Descovy 2016]. Oral administration of TAF results in lower circulating levels of tenofovir in plasma and affects markers of renal toxicity and bone mineral density less adversely [Sax et al. 2015; Mills et al. 2016; Pozniak et al. 2016]. Bioequivalence studies in healthy volunteers show that the TAF 10-mg dose administered with COBI 150 mg is equivalent to the TAF 25-mg dose without COBI [Zack et al 2016a; Zack et al. 2016b]. A switch study showed good maintenance of viral suppression when changing TDF/FTC to TAF 10 mg/FTC if the third drug was a boosted PI or TAF 25 mg/FTC if the third drug was an unboosted NNRTI or INSTI [Gallant et al. 2016]. (Note that TAF 10 mg alone and TAF 10 mg/FTC are not currently FDA-approved.) Until further safety data are available, this Committee has not included TAF 25 mg/FTC in combination with COBI or RTV as recommended regimens and recommends caution when using TAF 25 mg/FTC with regimens that contain either COBI or RTV in the setting of creatinine clearance (CrCl) <50 mL/min.

COBI-boosted DRV was approved based on bioavailability studies [Prescobix 2018; Kakuda et al. 2014] and has demonstrated comparable efficacy to RTV-boosted DRV in a single-arm study [Tashima et al. 2014]. However, because COBI-boosted DRV has not yet been studied in randomized clinical trials, it has a lower evidence strength. COBI-boosted ATV showed non-inferiority when compared with RTV-boosted ATV with a TDF/FTC backbone in a randomized double-blind study [Gallant et al. 2013].

All of the currently recommended preferred regimens have similar virologic efficacy when measured by an “on-treatment” metric, but adherence, the potential for drug interactions, and tolerability under real-life conditions may inform the choice of preferred versus alternative versus other regimens (see the Available ART Regimens section of this guideline).

The following general conclusions can be drawn based on currently available evidence from a number of pivotal studies:

When abacavir/lamivudine (ABC/3TC) is used as a backbone with EFV or boosted ATV, time to failure was shorter in the ≥100,000 copies/mL viral load stratum when compared with a backbone of TDF/FTC [Sax et al. 2011; Post et al. 2010; Sax et al. 2009].

General Considerations with Initial ART Regimens

The recommended antiretroviral therapy (ART) regimens should work well for the majority of properly selected patients, but some circumstances may make one regimen more favorable than another for a given individual. In general, an integrase strand transfer inhibitor (INSTI)-based regimen will be the best option for most patients [Lee et al. 2014; Mills et al. 2016]. To date, no resistance has been reported in ART-naïve patients treated with dolutegravir (DTG), suggesting that this ARV may be an excellent choice, particularly given its tolerability and lack of drug-drug interactions [Wainberg and Mesplede 2015]. Regimens containing a boosted-PI or DTG may be more appropriate when adherence is a concern given the higher barrier to resistance. For urgent treatment when genotypic information is not yet available, for example acute symptomatic infection, or advanced HIV with an opportunistic infection, some experts would use both DTG and boosted-DRV together with the NRTI backbone given the possibility of transmitted NRTI-resistance. Consultation with an experienced HIV care provider is recommended when choosing a regimen for patients with extensive comorbidities, impaired renal function, HBV or HCV co-infections, or very high viral loads.

KEY POINT

INSTI-based regimens are generally the best choice for most patients because of tolerability and durability.

Early clinical trials in HIV used surrogate markers, such as viral load and CD4 cell count, or clinical end points, such as morbidity and mortality, to demonstrate superiority of new therapies over the “gold standard” treatment of the era. One of the trials that led to the 1996 approval of indinavir (IDV) compared IDV alone versus zidovudine (ZDV) plus lamivudine (3TC) versus ZDV plus 3TC plus indinavir (IDV) in ZDV treatment-experienced patients, given that, at the time, dual-nucleoside (or nucleotide) analogue reverse transcriptase inhibitor (NRTI) treatment was considered acceptable [Gulick et al. 1997]. As treatment has evolved and become more effective, the use of clinical end points has become challenging; most trials in the current era of HIV therapy are powered to detect non-inferiority when compared with standard of care. For a variety of reasons, including cost and complexity, it would be impractical to conduct head-to-head comparisons of all available regimens. Some single-tablet regimens and fixed-dose combinations (FDCs) have been approved primarily based on bioequivalence studies when compared with the individual components, such as tenofovir disoproxil fumarate/emtricitabine/efavirenz (TDF/FTC/EFV), abacavir/lamivudine/dolutegravir (ABC/3TC/DTG), tenofovir alafenamide/emtricitabine/rilpivirine (TAF/FTC/RPV), TAF/FTC, and cobicistat/darunavir (COBI/DRV).

Some of the cutoff values used for comparisons, such as viral load <100,000 copies/mL or CD4 cell count ≥200 cells/mm3, are somewhat arbitrary. For example, most studies including RPV show that its efficacy is diminished when initiated at viral loads ≥100,000 copies/mL, and one showed that RPV worked even less well than EFV-based therapy at a viral load of ≥500,000 copies/mL [Domingo and Ribera 2013].

Some agents have been approved based on non-inferiority to the relatively less well-tolerated TDF/FTC/EFV regimen, which is, nevertheless, a potent and effective regimen for those who tolerate it well. The higher prevalence of non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance mutations when transmitted drug resistance occurs has prompted most experts to avoid NNRTI-based regimens if treatment is indicated prior to the availability of genotypic information [Panichsillapakit et al. 2016; Rhee et al. 2015; Stekler et al. 2015]. Although co-formulated TDF/FTC/COBI/EVG is approved for use at any starting viral load, reports of failure, with resistance, have been documented at very high baseline viral loads over 1,000,000 copies/mL [Rhee et al. 2015; Adams et al. 2016].

A paucity of data is available demonstrating how different antiretrovirals (ARVs) perform based on race and gender, although studies have suggested, for instance, that ritonavir (RTV)-boosted DRV is less well tolerated in women than in men and that blacks have higher discontinuation rates on RTV-boosted DRV compared with other populations [Smith et al. 2012; Currier et al. 2010].

Specific Factors to Consider and Discuss with Patients

Before initiating antiretroviral therapy (ART), the following factors are important to consider and discuss with patients.

Age: As individuals with HIV age, they have a higher prevalence of comorbidities than younger patients and are likely to be on more non-HIV-specific medications, particularly cardiovascular or gastrointestinal agents, posing a higher risk for adverse interactions [Marzolini et al. 2011]. For patients over 50 years of age, careful regimen selection with the use of integrase strand inhibitors (INSTIs) when possible, rather than cytochrome P450 inhibitors such as cobicistat (COBI) or ritonavir (RTV), can help minimize interactions, while using tenofovir alafenamide (TAF) can lower the risk of renal and bone toxicity.

Comorbidities: Assessment for existing cardiovascular risk, renal disease or risk factors for the development of renal disease, hepatic disease, bone health, mental health, and substance use should be performed.

Cost: Single-tablet regimens may be favorable because of the lower copays that could be associated with fewer prescriptions. Conversely, the individual components of these regimens may be available generically as separate pills.

Dosing requirements (daily versus twice daily): Most patients express a preference for once-daily dosing, especially those who are not taking other medications or are taking other medications that are dosed once daily. If patients are already on twice-daily dosing of other medications and report no adherence issues, twice-daily dosing is an acceptable option.

Drug-drug interactions: Some key interactions exist (Table 5, below), such as avoiding use of proton-pump inhibitors (PPIs) with rilpivirine (RPV), which is especially important to discuss with patients, given the availability of over-the-counter PPIs and the possibility that these drugs may be prescribed by someone other than the HIV care provider. To avoid unnecessary regimen changes once started, even patients who are not currently on PPIs should be asked whether they have needed PPIs in the past or may need them in the future.

RTV and COBI have many significant and important interactions, including with cardiac medications. Methadone maintenance requirements may also change with some antiretroviral agents (ARVs). A detailed review of all medications, including over-the-counter medications or supplements, is mandatory. Using automated drug-drug interaction software embedded in the electronic medical record or consulting an up-to-date database, such as HIV InSite’s Database of Antiretroviral Drug Interactions, for interactions with currently prescribed medications BEFORE prescribing a regimen, can help avoid serious problems.

ATV: In treatment-naïve patients on boosted ATV, H2-blockers should be either taken simultaneously with ATV or, if simultaneous dosing is not possible, separated from ATV by 10 hours; prescribe no more than 20 mg of famotidine or equivalent for one dose and no more than 40 mg twice daily of famotidine or equivalent for daily dose

RPV: Use with caution; administer at least 12 hours before or at least 4 hours after RPV

Inhaled steroids; statins

COBI; RTV: Alternatives or dose adjustments may be needed

Consult the package inserts for drug-drug interactions between specific statins and ARVs

Polyvalent cations [a]

DTG: Take 2 hours before or 6 hours after DTG; calcium-containing antacids or iron supplements may be taken simultaneously if taken with food

Aluminum, calcium, magnesium, or iron in some antacids or vitamin preparations.

For emergency contraception, other oral combinations, and patch, ring, or injectable formulations, please refer to package insert for specific ARV for dosing instructions and safety information

Food requirements: Because patients may have a strong preference for taking medication with or without food, it is important to discuss which pills must be taken on an empty stomach, which must be taken with food, and which can be taken with or without food, as listed in Box 1, below.

Known side effects and toxicities: Review known and potential side effects in advance.

Number of pills: Some patients feel strongly that the fewer the number of pills, the better. For other patients, the greatest concern may be the ability to take all pills (regardless of the number) together once daily. Sometimes using individual agents rather than a multi-agent FDC or single-tablet regimen may be attractive depending on pill size. In rare cases, patients who either cannot or will not swallow pills may need liquid formulations or pill crushing. Table 6, below, presents an abbreviated summary of commonly used ARVs and their availability in liquid formulation and/or the acceptability of crushing or dissolving them prior to ingestion. A full list that gives greater detail is available.

Pill size: Use images or real examples to give patients an idea of pill size BEFORE they fill the prescription (examples of visual guides include those of AIDSinfo and HIV i-Base). TAF/FTC/BIC and TAF/FTC/RPV are the smallest single-tablet regimens.

Special Considerations for Comorbid Conditions

Bone disease: TDF causes a decrease in bone mineral density in all patients after initiation of therapy and should be used with caution in patients with pre-existing severe osteoporosis [Stellbrink et al. 2010; McComsey et al. 2011; Perrot et al. 2009]. Some experts recommend baseline bone densitometry screening for osteoporosis in postmenopausal women and in men and transgender women older than 50 years who have HIV [Aberg et al. 2014]. The tenofovir alafenamide (TAF) formulation available currently in tenofovir alafenamide/emtricitabine (TAF/FTC), tenofovir alafenamide/emtricitabine/cobicistat/elvitegravir (TAF/FTC/COBI/EVG), tenofovir alafenamide/emtricitabine/bictegravir (TAF/FTC/BIC), and tenofovir alafenamide/emtricitabine/rilpivirine (TAF/FTC/RPV), is a better alternative with less bone toxicity [Pozniak et al. 2016; Bonora et al. 2016].

Cardiovascular Risks: Cobicistat (COBI)- or ritonavir (RTV)-containing regimens typically elevate lipids; tenofovir disoproxil fumarate (TDF)-containing regimens can have a beneficial effect [Souza et al. 2013]. Abacavir (ABC) has been associated with a higher risk of myocardial infarction in some studies [D:A:D Study Group et al. 2008; SMART/INSIGHT Study Groups et al. 2008; Obel et al. 2010; Choi et al. 2011; Marcus et al. 2016], whereas other studies have not confirmed this association [Bedimo et al. 2011; Ribaudo et al. 2011; Ding et al. 2012; Brothers et al. 2009]. Based on the available data, ABC should be used with caution in those with multiple cardiac risk factors or known coronary heart disease; however, the absolute risk of myocardial infarction remains low, and no clear causality has been established. In the appropriate clinical setting, such as a patient with impaired renal function, the use of ABC would be acceptable [Llibre and Hill 2016]. Clinicians should be made aware of the conflicting study data and share this information with patients.

Mental health and substance use: Modifiable factors that may influence adherence should be addressed.

KEY POINT

Neither mental health nor substance use disorders are contraindications to initiating therapy, although, in some cases, delay of initiation may be appropriate (see NYSDOH AI guideline When to Initiate ART).

Renal function: TDF can cause renal tubular dysfunction, such as acquired Fanconi syndrome [Karras et al. 2003; Zimmermann et al. 2006]. The risk of renal impairment has been shown to be elevated in patients with pre-existing renal disease, longer treatment duration, low body weight, and when used in conjunction with RTV- or COBI-boosted regimens [Gervasoni et al. 2013; Mocroft et al. 2016]. In general, full-dose TDF should be used with caution in patients with baseline creatinine clearance (CrCl) <70 mL/min and should be adjusted or changed to an alternative agent if CrCl decreases to <50 mL/min. Use of the TAF formulation is a better choice in these patients. As noted above, TAF 25 mg/FTC should be used with caution in boosted regimens when CrCl is <50 mL/min.

Both RTV-boosted atazanavir (ATV/r) and lopinavir/RTV (LPV/r) have also been independently associated with a greater decrease in renal function over time compared with NNRTI-based regimens [Goicoechea et al. 2008; Quesada et al. 2015]. COBI, and to a lesser extent dolutegravir (DTG), can inhibit the excretion of creatinine, with expected elevations of creatinine at initiation of therapy. However, such increases are not clinically relevant and do not significantly affect glomerular filtration rate [German et al. 2012; Lepist et al. 2014; Koteff et al. 2013].

Although DTG is highly bound to plasma proteins and therefore is unlikely to be removed by dialysis, it has not been studied in this population [Tivicay 2013]; therefore, raltegravir (RAL) or a boosted-protease inhibitor (PI) with renally-adjusted lamivudine (3TC) lamivudine and either ABC or once weekly TDF are usually the regimens of choice in this setting.

Very high viral loads (>750,000 copies/mL): In some cases, experts will recommend use of both boosted DRV and DTG when the viral load is very high, with possible simplification once viral suppression is achieved. Numerous switch studies have demonstrated the safety of simplifying ART regimens in suppressed patients with no pre-existing resistance [Cazanave et al. 2015; Arribas et al. 2014; Mills et al. 2013; Fisher et al. 2009]. Consultation with an experienced HIV care provider in these situations is helpful.

KEY POINTS

COBI and DTG can both cause decreased tubular excretion of creatinine and will dependably cause a slight increase in measured creatinine.

ABC has been associated with a higher risk of myocardial infarction in some studies, although not in others. No clear causal link has been established.

Boosted PIs and COBI-boosted EVG are associated with more hyperlipidemia than unboosted INSTIs.

Pre-ART-Initiation Laboratory Testing

Baseline CD4 cell count: Some regimens should not be used when the CD4 count is <200 cells/mm3 because of an increased risk of treatment failure in this population (see Table 7, below). When Pneumocystis jiroveci pneumonia (PCP) prophylaxis is indicated, it may be prudent to defer antiretroviral therapy (ART) for 7 to 10 days if 2 medications that may cause rash are going to be started, such as trimethoprim-sulfamethoxazole (TMP-SMX) and efavirenz (EFV).

Co-infections: Hepatitis B virus (HBV), hepatitis C virus (HCV), and tuberculosis (TB) infection status should be assessed. The ART regimen for those with chronic HBV infection should treat both HIV and HBV when possible (see NYSDOH AI guideline HBV-HIV Coinfection). For those planning concurrent HCV treatment or treatment for active TB, drug-drug interactions will play an important role in the selection of a regimen.

Creatinine clearance: Some antiretroviral agents (ARVs) are contraindicated below a given creatinine clearance (CrCl) level, and some may need adjustments that require the use of individual elements of fixed-dose combination or a single-tablet regimen rather than the single-tablet version of the drug. See Table 8: ARV Dose Adjustments for Renal and Hepatic Impairment for more information.

HIV genotypic resistance profile: Genotypic resistance testing that includes the protease and reverse transcriptase genes should be obtained at diagnosis (or initial visit if not done previously) [Borroto-Esoda et al. 2007; Kuritzkes et al. 2008]. Consultation with a care provider experienced in ART management is warranted when patients have baseline resistance that requires treatment with a regimen other than the listed preferred or alternative regimens. If treatment is indicated prior to the availability of genotypic resistance testing, non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens should be avoided because of the higher prevalence of transmitted resistance in NNRTIs versus protease inhibitors (PIs) or integrase strand transfer inhibitors (INSTIs) [Panichsillapakit et al. 2016; Rhee et al. 2015; Stekler et al. 2015]. In this situation, for example symptomatic acute infection or advanced HIV with an opportunistic infection, some experts would include DTG, boosted-DRV or both together with the NRTI backbone given the possibility of transmitted NRTI-resistance, with possible simplification once genotypic information is available. Because of the low prevalence, to date, of transmitted integrase resistance in ART-naïve patients [Volpe et al. 2016; Garcia-Diaz et al. 2014], routine integrase resistance testing is not recommended in these patients. However, in cases where integrase resistance is suspected, this test can be ordered as a supplement to protease and reverse transcriptase testing.

All Recommendations

On May 18, 2018, the FDA and the DHHS Antiretroviral Guidelines Panels issued statements in response to preliminary results from a study that reported increased risk of neural tube defects in babies born to mothers taking DTG-based ARV drug regimens at the time of conception [AIDSinfo 2018; FDA 2018].

Until more data become available, DTG-containing regimens should be avoided in any HIV-exposed individual who is or could become pregnant and is not using effective contraception. If there are no alternatives to DTG for individuals of child-bearing potential, then clinicians should strongly advise the use of effective contraception and should obtain a pregnancy test before initiating treatment.

Baseline testing is not recommended for either integrase resistance or tropism. (A3)

For patients who have delayed initiation of ART and have engaged in high-risk behaviors associated with acquisition of HIV superinfection, genotypic resistance testing should be repeated before choosing the ART regimen. (B3)

Clinicians or clinical staff should follow up, by telephone or other methods, within 2 weeks after treatment initiation to assess tolerance and adherence. Adherence should be reinforced at regular intervals. (A3)

Clinicians should obtain a viral load test within 4 weeks after initiation to assess response to therapy. (A3)

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